Suboptimal response in CML linked to Gleevec uptake in cells

February, 2008 – Australian researchers have confirmed the protein involved in Gleevec’s transport into chronic myelogenousleukemia (CML) cells and have shown that it is the activity of this protein which is a key determinant of response in CML patients.Dr. Timothy Hughes, Department of Hematology, Royal Adelaide Hospital, Adelaide, Australia, and his colleagues have recently reported in the journal, Blood, that “Most CML patients who have a suboptimal response to imatinib have low OCT-1 activity: higher doses of imatinib may overcome the negative impact of low OCT-1 activity”. Debra L. White, a PhD student in Dr. Hughes lab, was the lead author of this paper.

December 29th, 2011 – The same group of Australian reseachers, lead by Timothy Hughes and Deborah White, report that 2/3 of CML patients that they studied had low OCT-1 levels. Those with low OCT-1 levels and low plasma levels of Gleevec, achieved the lowest rates of major molecular response and were at highest risk for imatinib failure compared to all other patients.See abstract/full text article (PDF).

The CML and GIST worlds are closely linked. Gleevec was originally developed for CML and GIST formed the second major indication for Gleevec. New findings in one often have important implications for the other. While the consensus of GIST experts is that 400 mg should be the starting dose for most GIST patients (with the exception of exon 9 patients), the Life Raft Group will present the results of an internal study of LRG patients in the LRG Newsletter next month.

Proteins that move drugs out of cells have been suspected to be a cause of resistance to cancer therapy for many years. “Multi-drug resistance” or MDR is the term used to describe the process where cancer cells are able to “pump” drugs out of the cell before the drug concentration is high enough to kill the cell. The ability of some cancer cells to increase the number/activity of these drug pumps can lead to resistance across a spectrum of drugs, hence the term “multi-drug resistance.” Normal genetic variations can also cause some people to have more or less effective “pump” transport.

Understanding of multi-drug resistance proteins has largely been limited to their role in pumping drugs out of tumor cells (drug efflux). Recently, several groups have demonstrated that drug transport into the cell (drug influx) might also be an important factor in multi-drug resistance, especially in patients treated with Gleevec.

In 2004, Julia Thomas and her colleagues at the University of Liverpool in the United Kingdom, were the first to describe the role of OCT-1 (sometimes written as hOCT-1) in transporting Gleevec into cells. They speculated on the clinical implications of their findings. “The net effect of these transport processes may be a decrease in the intracellular concentration of imatinib (Gleevec).” The consequences are that cells might become resistant to Gleevec.

Lucy Crossman, Brian Druker, and Michael Deininger extended the laboratory work of the Liverpool team to CML patients. In a letter to the editor of Blood, they gave a short report on their experience with a small group of CML patients. They divided the patients into responders (achieved a complete cytogenetic response to Gleevec within the first year) and nonresponders (remained at least 65% Philadelphia-chromosome positive during the first ten months of Gleevec).

The Crossman team found that baseline expression of hOCT1 (the influx pump) was variable and not significantly different from healthy bone marrow donors. Interestingly however, the pre- Gleevec expression level of hOCT1 in non-responders was one-eighth that was seen in responders (P=.005). Once on Gleevec, six of the non-responders had a further twofold decrease in the expression of hOCT1 compared to baseline. The implications were that in the nonresponders, not as much Gleevec was being pumped into the tumor cells.

Crossman noted in her correspondence to the editor, “Since hOCT1 actively transports imatinib (Gleevec) into cells, patients with low baseline expression of hOCT1 may be unable to achieve adequate intracellular concentrations of imatinib, and hence fail to achieve a cytogenetic response. Although our study is small, our observations add weight to Thomas, et al.’s proposal that differential expression of hOCT1 may affect patients’ responses to imatinib. We believe that further work is warranted to explore the interaction of hOCT1 and other drug transporters as a cause of primary cytogenetic resistance to imatinib.”

In the current Australian study, White, Hughes and their colleagues designed an assay to measure OCT-1 activity in the blood of CML patients enrolled in either the TIDEL trial or the TOPS trial for CML patients. This assay provides a measure of the actual activity of the OCT-1 protein in the transport of Gleevec into the cell.

An examination of 132 patients enrolled in both trials revealed a wide variation in OCT-1 activity (range 0 to 31.2 with a median of 8.2). Five of the patients had negligible OCT-1 activity.

Survival in imatinib-treated chronic phase CML (the initial phase of CML) has been previously shown to correlate with the depth of response to imatinib. Patients with more residual disease during treatment do not do as well. Difference landmarks have been established in CML to indicate when a patient is having a “suboptimal response”. In this study, the Australian team showed that most of the CML patients that had a suboptimal response had low OCT-1 activity resulting in inadequate concentrations of Gleevec in cells.

The OCT-1 activity was compared with molecular response over the first 24 months of imatinib therapy in 56 patients in the TIDEL trial. The median OCT-1 activity level was 7.2 ng/200,000 cells for this group of patients. Patients were grouped into high and low OCT-1 activity with the upper half of patients considered high OCT-1 activity and the lower half of patients considered to have low OCT-1 activity. Patients with high OCT-1 activity achieved significantly higher molecular response compared to patients with low OCT-1 activity (P=0.005 at 24 months).

To assess whether a higher dose of Gleevec could overcome the effects of low OCT-1 activity (poor Gleevec transport into tumor cells), the authors looked at the actual Gleevec dose patients received. They noted that “Separating patients into those averaging 600 mg and those failing to do so revealed patients with a high OCT-1 activity achieved good molecular responses regardless of dose. In contrast, the molecular response of those patients with low OCT-1 activity was highly dose dependent; with patients receiving 600 mg achieving significantly better molecular response by 24 months (P =.005)… These data indicate that dose is a critical determinant of long-term molecular response in the low OCT-1 activity cohort, but patients with a high OCT- 1 activity generally perform well regardless of dose.”

In the study, only 18 percent of patients receiving 600 mg or less of Gleevec and having low OCT-1 activity had a Major Molecular Response (MMR) by 24 months compared to 83 percent of patients in the same dose range but having high OCT-1 activity.

The Australian Group had previously shown that in 62 CML patients, there was a marked variability in their intrinsic sensitivity to Gleevec. When their cancer cells were tested to see how much Gleevec was required to inhibit the Crkl protein (inhibition of Crkl is used as a surrogate for inhibition of Bcr/ Abl, the protein that drives CML) by 50 percent (IC50), they found that the IC50 ranged from 0.375 to 1.8 μM (median, 0.6 μM). In a latter paper, they reported that reduced OCT-1 activity was the cause of low in-vitro sensitivity to imatinib.

In summarizing their work, the authors noted that “The data presented here demonstrates clearly that dose is an important factor for overcoming suboptimal response in low OCT-1 activity patients. These findings indicate a potential role for increased imatinib dose up front in those patients found to have low OCT-1 activity prior to imatinib start. Intolerance to higher dose imatinib in these patients may be a trigger to switch to an ABL kinase inhibitor that is not dependent on OCT-1 for its uptake into cells (AMN107 is not dependent on OCT-1 activity for cellular uptake)…. Importantly, using this functional assay to determine OCT-1 activity at the time of diagnosis may identify patients likely to respond well to standard-dose imatinib and those who would be most likely to benefit from a higher dose of imatinib.”

Further support for the importance of OCT-1 in CML was provided by the University of Liverpool group (with L. Wang as the lead author), in an article published in June 2007 in Clinical Pharmacology & Therapeutics. In analyzing 70 consecutive imatinib-naïve CML patients seen between October 2000 and 2005 Wang and colleagues report that the pretreatment expression level of hOCT1 is critical in determining outcome. The authors suggest “that a crucial determinant of cytogenetic response may be the early achievement of high intracellular imatinib concentrations. Finally, in regression analysis, we demonstrate that hOCT1 expression is a critical determinant of the outcome of imatinib therapy, in comparison with other easily measured clinical and hematological parameters.” The results of their study are reported in Figure 2.

While the OCT-1 story is less developed as it pertains to GIST, it seems reasonable that the same mechanisms are applicable. As a practical measure, Dr. Hughes offered this advice “I would certainly avoid OCT-1 inhibitors (prazosin, procainamide, progesterone) if I were on imatinib and looking for better efficacy.

Alert: Based on the apparent importance of OCT-1 in getting Gleevec into tumor cells, it seems prudent that patients talk to their doctors about avoiding inhibitors of OCT-1 activity. Known inhibitors of OCT-1 are listed below.

• Prazosin (trade names Minipress ®,Vasoflex® and Hypovase®) is a medication used to treat high blood pressure. It belongs to the class of alphaadrenergic blockers, which lower blood pressure by relaxing blood vessels.

• Procainamide (trade names Pronestyl ®, Procan®, Procanbid®) is a pharmaceutical antiarrhythmic agent used for the medical treatment of cardiac arrhythmias. Procanbid® will no longer be manufactured.

• Progesterone is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species. Progesterone belongs to a class of hormones called progestogens, and is the major naturally occurring human progestogen. Progesterone should not be confused with progestins, which are synthetically produced progestogens.

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